Inflammatory skin diseases such as atopic dermatitis, urticaria and especially psoriasis still constitute a great problem for the affected patients as there are today no effective therapies.
Psoriasis is a common chronic inflammatory dermatosis with a global distribution; it has been estimated that about 1.5% of the population in the western countries can be expected to suffer from the disease during their lifetime. A number of different clinical patterns of psoriasis are acknowledged, the most common being plaque psoriasis.
Hyperproliferation, inflammation with massive infiltration of leucocytes and disturbances in cell differentiation are the typical characteristics of psoriatic skin. The number of basal cells is vastly increased which reduces the turn-over time for the epidermis from the normal 27 days to 3-4 days. The normal events of cell maturation and keratinization do not occur. This proliferation of keratinocytes occurs both in involved and non-involved psoriatic skin but is most pronounced in the plaques. The inflammatory infiltrate from psoriatic lesions has been found to consist predominantly of mononuclear T lymphocytes. There is a disturbed T cell function also in the circulating blood, which implies a possible cell-mediated immunological abnormality in psoriasis. The phagocytes that can be identified histologically in the psoriatic lesion, neutrophils in particular, suggest a role for the chemotactic inflammatory mediators in the pathology of psoriasis. Among these interleukin-1, -6 and -8, leukotriene B.sub.4 and PAF have been isolated in pathological amounts in the affected skin.
There is a number of different therapies of psoriasis of varying effectiveness, none being perfect. Among the antipsoriatic drugs of natural origin can be mentioned coal tar, dithranol, psoralens, retinoids and cyclosporin A. In addition to said more established therapies can also be mentioned the use of podophyllotoxin, a lignan which can be isolated from Podophyllum species, polyunsaturated fatty acids, such as eicosapentaenoic acid and gammalinolenic acid, and colchicine, an alkaloid from the crocus plant. The use of essential fatty acids in atopic dermatitis and psoriasis, respectively, are described by Wright, S., British Journal of Dermatology 125, 503-515, 1991.
In the traditional medicine of Honduras the name Calaguala is used for the extract of a number of closely related Polypodium species, including P. decumanum Willd., P. aureum (or P. leucatomos), P. lowei C. Chr., P. loriceum L., P. triseriale Sw., P. fraxinifolium Jacq. and P. dissimile L (Molina, personal communication, 1991). A decoction or infusion of the Calaguala plant has been used to treat a number of diseases including peptic ulcer, kidney problems, diarrhoea and arthritis or other pains in joints and tendons.
Over the last two decades several clinical trials have been performed on calaguala in the treatment of psoriasis, as well as atopic dermatitis (Vargas Gonzales, J. P., et al., Acta Pediatric. Esp. 46(1), 556-561, 1988) and vitiligo (Gonzales, S., et al., J. Invest. Derm. 102(4), 651, 1994).
Platelet activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a phospholipid derived mediator with a diversity of biological effects. PAF is released from various cell types, including platelets, neutrophils, monocytes and endothelial cells. In addition, several cell types, including neutrophils, are known to express specific PAF receptors on their cell membrane. In vitro PAF exhibits effects, including aggregation and degranulation of leukocytes and inhibition of lymphocyte proliferation. In vivo effects include hypotension, acute renal failure and increase in vascular permeability. PAF is thought to be associated with a number of pathological conditions, such as shock, airway hypersensitivity and asthma, inflammation of many different types, psoriasis, arthritis and graft rejection and various cardiovascular disorders especially ones associated with thrombosis, blood coagulation and platelet aggregation.
A large number of natural and synthetic PAF receptor antagonists has been discovered which show different physiological effects, but to date they have been of limited usefulness for pharmaceutical purposes. The use of some compounds in the treatment of asthma is, however, currently being evaluated. As the PAF antagonist therapy is relatively new, more research is still needed for the judgement of therapeutic benefit for specific indications. It is believed that safe and potent compounds will have a substantial role in therapeutical treatments.
Perhaps the best known of all PAF antagonists is the ginkgolide BN 52021 which was isolated from the "fossil tree" Ginkgo biloba in the late 60's. It is a specific PAF receptor antagonist and has shown anti-inflammatory properties in several in vivo and in vitro models. For the potential oral treatment of chronic inflammatory diseases, the synthetic hetrazepine derivative BN 50730 was later developed. It shows a several ten-folds more potent PAF antagonistic activity in vitro. (Guinot, P. in Clinical Reviews in Allergy 12, 397-417, 1994.)
It has been suggested that PAF contributes to the inflammatory aspects of psoriasis (Cunningham, 1990). Factors that implicate its role in the pathogenesis and symptoms are that PAF has been isolated in elevated amounts on psoriatic skin, that injection of PAF causes vasodilation and increased vascular permeability, and that PAF is chemoattractant mainly to neutrophils.
Recently, PAF activity has been measured in blood plasma of patients with psoriasis using a radioimmunoassay technique (Izaki et al., British Journal of Dermatology 136, 1060-1064, 1996). It was shown that levels of PAF were significantly elevated in patients with psoriasis and that when these patients were treated with conventional anti-psoriatic methods the levels were decreased. Also, the decrease was correlated with a clinical improvement. It is concluded that PAF has a role in the acute phase of psoriatic and leucotactic inflammation.
In another study, chemotactic responsiveness of pheripheral blood eosinophils from healthy subjects and from patients with inflammatory dermatoses (psoriasis, atopic dermatitis) was determined. It was found that chemotactic responsiveness was significantly enhanced in severely affected patients and that this increase was not related to a specific disease. The increased responsiveness in peripheral eosinophils to PAF is suggested to be related to altered receptor expression during cutaneous inflammation (Morita et al. 1989).